In recent years, new antiinflammatory drugs, the so called coxibs or cyclooxygenase-2 (COX-2) inhibitors, which intend to avoid the commonly described gastric effects of non-steroidal antiinflammatory drugs (NSAIDs), have reached the market. Both kinds of drugs act by inhibiting cyclooxygenase, which is an enzyme that takes part in the arachidonic acid cascade by catalyzing the formation of substances such as prostaglandins (PGE2, PGD2, PGF2), prostacyclin (PGI2) and thromboxane A2 (TXA2), substances that, due to their vasoactive and inflammatory properties, are involved in numerous inflammatory processes, both acute and chronic.
The great difference between both kinds of drugs lies on the cyclooxygenase isoform upon which they act. In the early 90's, two cyclooxygenase isoforms, COX-1 and COX-2, were described. COX-1 is the constitutive form, present in many tissues, but preferentially in the stomach, kidney and platelets. Its inhibition is responsible for the gastric, renal and antiplatelet effects of NSAIDs, given that it leads to a reduction in the levels of prostaglandins, which at gastric level play a key role in the protection of the mucosa. On the other hand, COX-2 is an inducible form which is expressed as a consequence of an inflammatory or mitogenic stimulus in a wide range of tissues such as macrophages, chondrocytes, fibroblasts and endothelial cells. Selective inhibition of this isoform, mechanism on which the coxibs are based, is expected to render drugs with improved gastric tolerance.
Furthermore, COX-2 inhibition has proved to be an effective mechanism for the treatment of pain, especially for the treatment of severe and moderate pain resulting for example from traumatisms, acute diseases or surgery.
In the treatment of severe and moderate pain, especially in hospitals, the use of parenteral formulations is preferred in order to achieve a more rapid onset of action. Despite the fact that an inappropriate management of post-operative pain can lead to serious complications, long hospital stays, slower recoveries and an increase in the use of medications, its treatment is not solved at present in a satisfactory way. Thus, the use of the drugs currently available for this indication is limited due to the side effects with which they are associated: conventional NSAIDs are related to the above mentioned gastric and antiplatelet effects, while opioids, which are still more effective in the treatment of pain, are associated with sedating effects, constipation and respiratory depression. Moreover, most of the coxibs that are nowadays on the market or under development show water solubility values that do not contribute in any way to the development of injectable formulations. Thus, the present availability of injectable formulations for the treatment of pain is limited. Therefore, there remain a great need to find new compounds with antiinflammatory and analgesic activity which can be administered by parenteral route.